Cancer is one of the primary causes of death in most advanced countries. In Japan, the cancer occupies almost 30% of the cause of death. Advancement of surgical treatment and radio therapeutics often allows for removal of the primary focus of a cancer. The still high morbidity is ascribed to the metastatic properties of cancers. In the current state, it is extremely difficult to cure the cancer with multiple metastases. One of the important targets of cancer treatment is thus to establish a method of suppressing metastasis of cancer, in addition to the conventional treatment of the primary focus. In this state, the mechanism of cancer metastasis is gradually being elucidated on the molecular level. The decomposition system of the extracellular matrixes has been noted as one of the metastatic processes.
Metastasis of a cancer represents the state that cancer cells released from a primary site are distributed to the whole body through the blood stream, are delivered live to another organ, and start multiplication in the tissue of the organ. In general, the tumor tissue is surrounded by a dense extracellular matrix. Enzymolysis of the extracellular matrix is necessary for distribution of cancer cells from the primary site. The extracellular matrix is composed of various macromolecules including collagen, elastin, fibronectin, laminin, and proteoglycan. MMP is a group of primary enzymes involved in enzymolysis of the extracellular matrixes. The MMP is activated and has enhanced enzyme expression in the process of vascularization in the cancer tissue or in the process of metastasis of the cancer, as described in Reference 1 cited below. A decrease in enzyme expression and inhibition of the enzymatic activity are thus expected to suppress invasion of cancer cells and thereby metastasis of cancers.
Reference 1
    ‘Retinoid-Mediated Suppression of Tumor Invasion and Matrix Metalloproteinase Synthesis’, Shoenermark M. P. et al, Annals New York Academy of Sciences, Vol. 878, pp 466-486, 1999
In the process of invasion of cancer cells into the macromolecules, collagenolysis is especially a critical step. Decomposition of the type IV collagen present on the basilar membrane of a blood vessel is necessary to allow cancer cells to invade into the blood vessel or to be released from the blood vessel. Liotta et al has found that the action of the type IV collagenolytic enzyme secreted by the cancer cells is an important factor to determine the cancer metastasis power. Gelatinase included in the MMP is an enzyme produced by fibroblasts, endothelial cells, and cancer cells and decomposes the matrixes of the type IV collagen, gelatin, and elastin. A substance having the inhibiting activity, for example, against gelatinase is expected to have the effects of suppressing vascularization in the cancer tissues and metastasis of cancers and to be effective for prevention and treatment of cancers and carcinomas.
Reference 2
    ‘Metastatic potential correlates with enzymatic degradation of basement membrane collagen’, Liotta L. A. et al, Nature, Vol. 284, pp 67-68, 1980
The reference 3 cited below has reported that the MMP plays an important role in decomposition of extracellular matrixes in various pathology including cancers, ulceration, rheumatoid arthritis, osteoporosis, and periodontitis. The activated MMP due to external stimuli like ultraviolet radiation decomposes essential components for maintaining the skin structure. The MMP has thus been specifically noted recently as an aging acceleration factor activated by ultraviolet radiation.
Reference 3
    ‘Matrix metalloproteinases as tissue destructive proteinases’, Mitsutoshi Nakata, Yasunori Okada, KOKYU (Respiratory), Vol. 18, No. 4, pp 365-371, 1999
The MMP inhibitors have thus been expected to have effects on treatment and symptomatic relief of the activated MMP-causing disorders and diseases and have been intensively studied for screening. Such inhibitors are disclosed in the following references:
JAPANESE PATENT LAID-OPEN GAZETTE No. 9-40552
JAPANESE PATENT LAID-OPEN GAZETTE No. 11-147833
PATENT LAID-OPEN GAZETTE No. 2000-226311
The object of the present invention is thus to provide an MMP inhibitor that has inhibiting activity against activation of MMP produced by high metastatic carcinoma cell strains and is effective for prevention and symptomatic relief of various activated MMP-causing disorders and diseases, such as metastasis of cancers.